Process for producting imidazo[1,2-b]pyridazine derivative

ABSTRACT

A process for easily and inexpensively producing an imidazo[1,2-b]pyridazin-3-ylsulfonamide derivative which has a substituent bonded to the 6-position carbon atom and is represented by the formula (II): 
     
       
         
         
             
             
         
       
         
         
           
             (wherein R represents lower alkyl, lower cycloalkyl optionally substituted by lower alkyl, lower alkenyl, or lower alkynyl), the process comprising reacting an imidazo[1,2-b]pyridazine compound represented by the formula (I): 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             (wherein X represents halogeno or lower alkyl optionally substituted by halogeno; Y represents hydrogen or SO 2 N═CH—NR 1 R 2 ; and Z represents halogeno or OSO 2 R 3 ) with an organometallic compound in the presence of a transition metal catalyst. The derivative is useful as an intermediate for herbicides.

TECHNICAL FIELD

This invention relates to a novel process for producing animidazo[1,2-b]pyridazine derivative having a substituent bonded to the6-position carbon atom which is used for producing a sulfonylureacompound having a fused heterocyclic ring useful as a herbicide, and anintermediate thereof.

BACKGROUND ART

Sulfonylurea compounds having a fused heterocyclic ring are known as aherbicide having a high herbicidal activity and high safety for crops(e.g., see JP-B H05-36439 and JP-A H01-139582). Among them, asulfonylurea compound having imidazo[1,2-b]pyridazine ring as a fusedheterocyclic ring is one of compound groups having a high activity,especially the present inventors found out that a compound having asubstituent bonded to the 6-position carbon atom ofimidazo[1,2-b]pyridazine ring has a high herbicidal activity againstweeds resistant to conventional sulfonylurea herbicides, and filed apatent application (JP Application No. 2003-6756). As a reaction forintroducing a substituent at the 6-position carbon atom ofimidazo[1,2-b]pyridazine ring, Journal of Antibiotics, 54 (3), 257-277,2001; Synthesis, (4), 595-600, 2001; JP-A H05-271233; JP-A H06-116272;JP-A H11-310581; JP-A H11-310582; JP-A 2000-198735; JP-A 2001-199889 andthe like are known.

The object of this invention is to provide a process for easily andinexpensively producing an imidazo[1,2-b]pyridazin-3-ylsulfonamidederivative having a substituent bonded to the 6-position carbon atomwhich is useful as a synthetic intermediate for herbicides.

DISCLOSURE OF INVENTION

To solve the above-mentioned problem, the present inventors madeextensive study to find out an easy and inexpensive production processof imidazo[1,2-b]pyridazin-3-ylsulfonamide compound having a substituentbonded to the 6-position carbon atom over the years, and as a result,found out that an imidazo[1,2-b]pyridazine derivative having asubstituent bonded to the 6-position carbon atom can be obtainedunexpectedly with a convenient operation and in good yield by reactingan imidazo[1,2-b]pyridazine derivative having a leaving group at the6-position with an organometallic compound under the presence oftransition metal catalyst. After further studying extensively based onthese knowledge, this invention was thereby completed.

That is, this invention relates to:

(1) A process for producing a compound represented by the formula (II):

wherein X represents a halogen atom or an optionally halogenated loweralkyl group, Y represents a hydrogen atom or SO₂N═CH—NR¹R² (wherein R¹and R² represent each lower alkyl group, or R¹ and R² may be combinedtogether with the adjacent nitrogen atom to form a heterocyclic ring),and R represents a lower alkyl group, lower cycloalkyl group which maybe substituted with lower alkyl, lower alkenyl group or lower alkynylgroup (also referred to hereinafter as Compound (II)), which comprisesreacting an imidazo[1,2-b]pyridazine compound represented by the formula(I):

wherein X and Y are as defined above, and Z represents a halogen atom orOSO₂R³ (wherein R³ represents an optionally fluorinated lower alkylgroup or phenyl group which may be substituted with lower alkyl) (alsoreferred to hereinafter as Compound (I)), with one or more compoundsselected from the organometallic compounds represented by the formula:

wherein R is as defined above, and M¹ represents an univalent metal, M²represents a divalent metal, M³ represents a trivalent metal and M⁴represents a tetravalent metal, and L, L′ and L″ are the same ordifferent and represent an anion, under the presence of transition metalcatalyst,

(2) The process according to the above-mentioned (1), wherein the metalof the transition metal catalyst is palladium, nickel or iron,

(3) The process according to the above-mentioned (1), wherein the metalof the transition metal catalyst is nickel,

(4) The process according to the above-mentioned (1), wherein the metalof the organometallic compound is magnesium or zinc,

(5) The process according to the above-mentioned (1), wherein R is alower alkyl group or lower cycloalkyl group which may be substitutedwith lower alkyl,

(6) The process according to the above-mentioned (1), wherein X and Zare a chlorine atom,

(7) The process according to the above-mentioned (1), wherein Y is ahydrogen atom and R is a lower alkyl group,

(8) The process according to the above-mentioned (3), wherein the metalof the organometallic compound is magnesium or zinc,

(9) The process according to the above-mentioned (8), wherein theorganometallic compound is a lower alkylmagnesium halide or alower-alkylzinc halide,

(10) The process according to the above-mentioned (9), wherein theorganometallic compound is a propylmagnesium halide or propylzinc halideand the nickel catalyst is [1,3-bis(diphenylphosphino)propane]nickel(II) dichloride or bis(triphenylphosphine)nickel (II) dichloride,

(11) A process for producing a sulfonamide compound represented by theformula (III):

wherein X represents a halogen atom or an optionally halogenated loweralkyl group and R represents a lower alkyl group, lower cycloalkyl groupwhich may be substituted with lower alkyl, lower alkenyl group or loweralkynyl group (also referred to hereinafter as Compound (III)), whichcomprises sulfonating with chlorosulfonic acid a compound represented bythe formula (IIa):

wherein X and R are as defined above (also referred to hereinafter asCompound (IIa)), which is obtained by reacting animidazo[1,2-b]pyridazine compound represented by the formula (Ia):

wherein X is as defined above, and Z represents a halogen atom or OSO₂R³(wherein R³ represents an optionally fluorinated lower alkyl group orphenyl group which may be substituted with lower alkyl) (also referredto hereinafter as Compound (Ia)), with one or more compounds selectedfrom the organometallic compounds represented by the formula:

wherein R is as defined above, and M¹ represents an univalent metal, M²represents a divalent metal, M³ represents a trivalent metal and M⁴represents a tetravalent metal, and L, L′ and L″ are the same ordifferent and represent an anion, under the presence of transition metalcatalyst, followed by converting to a sulfonyl chloride with phosphorusoxychloride, then reacting with ammonia, and

(12) A process for producing a sulfonamide compound represented by theformula (III):

wherein X represents a halogen atom or an optionally halogenated loweralkyl group and R represents a lower alkyl group, lower cycloalkyl groupwhich may be substituted with lower alkyl, lower alkenyl group or loweralkynyl group, which comprises hydrolyzing under the presence of acid oralkali a compound represented by the formula (IIb):

wherein X and R are as defined above and Y′ represents SO₂N═CH—NR¹R²(wherein R¹ and R² represent each lower alkyl group, or R¹ and R² may becombined together with the adjacent nitrogen atom to form a heterocyclicring) (also referred to hereinafter as Compound (IIb)), which isobtained by reacting an imidazo[1,2-b]pyridazine compound represented bythe formula (Ib):

wherein X and Y′ are as defined above, and Z represents a halogen atomor OSO₂R³ (wherein R³ represents an optionally fluorinated lower alkylgroup or phenyl group which may be substituted with lower alkyl) (alsoreferred to hereinafter as Compound (Ib)), with one or more compoundsselected from the organometallic compounds represented by the formula:

wherein R is as defined above, and M¹ represents an univalent metal, M²represents a divalent metal, M³ represents a trivalent metal and M⁴represents a tetravalent metal, and L, L′ and L″ are the same ordifferent and represent an anion, under the presence of transition metalcatalyst.

MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in detail below.

Given the term “lower” in the lower alkyl group, lower alkenyl group,lower alkynyl group etc. in this specification, these alkyl group andthe like are meant to be composed of 1 or 2 to 6 carbon atoms,preferably 1 or 2 to 4 carbon atoms. For example, a linear or branchedC₁₋₆ alkyl group, C₂₋₆ alkenyl group and C₂₋₆ alkynyl group areexemplified. In addition, the “lower cycloalkyl group” means C₃₋₇cycloalkyl group having 3 to 7 carbon atoms.

In the above-mentioned formulas (I), (Ia) and (Ib), X represents ahalogen atom or an optionally halogenated lower alkyl group, and the“halogen atom” in “halogen atom” and “optionally halogenated lower alkylgroup” includes, for example, fluorine, chlorine, bromine, iodine etc.Examples of the “lower alkyl group” in “optionally halogenated loweralkyl group” include C₁₋₆ alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, s-butyl, t-butyl etc. Examples of preferablesubstituent as X include fluorine, chlorine, methyl, ethyl,trifluoromethyl and the like.

When R¹ and R² of SO₂N═CH—NR¹R² for Y and Y′ in the above formulas (I)and (Ib) represent independently a lower alkyl group, the “lower alkylgroup” includes, for example, C₁₋₆ alkyl group such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl etc., and the“heterocyclic ring” in case that “R¹ and R² are combined together withthe adjacent nitrogen atom to form a heterocyclic ring” includes, forexample, a 3- to 10-membered (preferably, 3- to 6-membered)nitrogen-containing heterocyclic ring such as azetidine ring,pyrrolidine ring, piperidine ring, and the like.

In the above-mentioned formulas (I), (Ia) and (Ib), the “halogen atom”for Z includes, for example, fluorine, chlorine, bromine, iodine etc.The “lower alkyl group” in the “optionally fluorinated lower alkylgroup” for R³ of “OSO₂R³” includes, for example, C₁₋₆ alkyl group suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyletc. The “lower alkyl group” of the “phenyl group which may besubstituted with lower alkyl” includes, for example, C₁₋₆ alkyl groupsuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl,t-butyl etc. Examples of preferable substituent as Z include a halogenatom, in particular, chlorine and bromine are preferred.

In the organometallic compounds represented by the formula:

and formulas (II), (IIa) and (IIb), examples of the “lower alkyl group”in the “lower alkyl group” and “lower cycloalkyl group which may besubstituted with lower alkyl” for R include C₁₋₆ alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl etc.Examples of the “lower cycloalkyl group” in the “lower cycloalkyl groupwhich may be substituted with lower alkyl” include C₃₋₇ cycloalkyl suchas cyclopropyl, cyclobutyl, cyclopentyl, etc. Examples of the “loweralkenyl group” include C₂₋₆ alkenyl such as ethenyl, 1-propenyl,2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, etc., and examples of the“lower alkynyl group” include C₂₋₆ alkynyl such as ethynyl, 1-propynyl,2-propynyl, 2-butynyl etc. The preferred substituent as R includesethyl, propyl, isopropyl and cyclopropyl.

As M¹ which represents an univalent metal in the above-mentionedorganometallic compounds, lithium, sodium, potassium, rubidium,univalent copper, and the like are exemplified. M² which represents adivalent metal include, for example, magnesium, calcium, strontium,barium, zinc, cadmium, mercury, divalent copper, divalent lanthanoidmetal and the like. M³ which represents a trivalent metal include, forexample, boron, aluminum, trivalent lanthanoid metal and the like. M⁴which represents a tetravalent metal include, for example, silicon,germanium, tin, lead, titanium, zirconium, cerium and the like.Preferred metal is an univalent or divalent metal, and in particular,magnesium or zinc is preferred.

The anions represented by L, L′ or L″ in the above-mentionedorganometallic compounds are the same or different and include, forexample, a halogen such as fluorine, chlorine, bromine, iodine etc.,C₁₋₆ alkoxy group such as methoxy, ethoxy, propoxy etc., phenoxy group,C₁₋₆ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl etc.,carboxylic acid anion such as acetate, trifluoroacetate, benzoate etc.,phenyl group, cyano group, hydroxy group and the like, or two of L, L′or L″ may be combined together to form a dialkoxide of diol such asethylene glycol and catechol. Preferred is a halogen.

Preferable examples of the organometallic compound include organicalkalimetallic compound, organic alkaline earth metallic compound,organozinc compound, organocupric compound, organosilicon compound andorganolead compound, and in particular, preferred are organomagnesiumhalide and organozinc halide.

The organometallic compound is usually commercially available orprepared from a halide such as alkyl halide, cycloalkyl halide, alkenylhalide, alkynyl halide, etc. and a metal simple substance, or it can beobtained by a metal exchange reaction of easily available organometalliccompound and other metal salt. Examples thereof include a preparation oforganozinc compound by a reaction of organolithium compound ororganomagnesium compound with zinc chloride, a preparation oforganotitanium compound by a reaction of organolithium compound ororganomagnesium compound with titanium chloride, a preparation oforganocerium compound by a reaction of organolithium compound ororganomagnesium compound with cerium chloride, a preparation oforganocopper compound by a reaction of organolithium compound ororganomagnesium compound with copper chloride, and the like.

Furthermore, the organometallic compound can be used with generating itfrom a halide such as alkyl halide, cycloalkyl halide, alkenyl halide,alkynyl halide, etc. and a metal simple substance in the system ofcoupling reaction with imidazo[1,2-b]pyridazines.

Examples of the transition metal catalyst include a transition metalsimple substance, a catalyst wherein transition metal is fixed on acarrier, a transition metal complex, a polymerized transition metal, atransition metal complex which is fixed in a microcapsule, and the like.Examples of the transition metal include titanium, vanadium, chromium,manganese, iron, cobalt, nickel, cupper, zirconium, niobium, molybdenum,ruthenium, rhodium, palladium, silver, hafnium, tantalum, tungsten,rhenium, osmium, iridium, platinum, gold etc., and preferred ispalladium, nickel or iron, and in particular, nickel is preferred.

In the case of complex, examples of ligand include a halogen anion suchas fluorine anion, chlorine anion, bromine anion, iodine anion, cyanoanion, alkoxy anion such as methoxy, ethoxy, isopropoxy etc., carboxylicacid anion such as acetate anion, trifluoroacetate anion etc., sulfonicacid anion such as methanesulfonate, trifluoromethanesulfonate,p-toluenesulfonate etc., amines such as ammonia, methylamine,ethylamine, dimethylamine, ethylenediamine, triethylamine, aniline,N,N-dimethylaniline etc., pyridine, 2,2′-bipyridyl, imidazole, alkoxidesof aminoalcohol such as ethanolamine, propanolamine etc., phosphinessuch as tributylphosphine, tricyclohexylphosphine, triphenylphosphine,1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane,1,4-bis(diphenylphosphino)butane etc., aminoalkylphosphines such as2-(dimethylamino)ethyldiphenylphosphine etc., alkoxides ofhydroxyalkylphosphine such as diphenyl(2-hydroxyethyl)phosphine etc.,carbon monoxide, ethylene, butadiene, cyclopentadienyl anion,1,5-cyclooctadiene, acetonitrile, benzonitrile, acetylacetonate anion,dibenzalacetone, and the like. The transition metal complex is composedof same or different 1 to 6 ligands selected from the above-mentionedligands.

The transition metal complex is preferably a palladium or nickel complexcontaining phosphines as a ligand such asbis(triphenylphosphine)nickel(II) dichloride,bis(triphenylphosphine)nickel(II) dibromide,[1,3-bis(diphenylphosphino)propane]nickel(II) dichloride,[1,3-bis(diphenylphosphino)propane]nickel(II) dibromide,bis(triphenylphosphine)palladium(II) dichloride,bis(triphenylphosphine)palladium(II) dibromide,[1,3-bis(diphenylphosphino)propane]palladium(II) dichloride,[1,3-bis(diphenylphosphino)propane]palladium(II) dibromide andtetrakis(triphenylphosphine)palladium, or an iron compound such asiron(II) chloride, iron(III) chloride or iron(III) acetylacetonate, andparticularly preferred are bis(triphenylphosphine)nickel(II) dichloride,[1,2-bis(diphenylphosphino)ethane]nickel(II) dichloride and[1,3-bis(diphenylphosphino)propane]nickel(II) dichloride.

The transition metal complex is usually commercially available orprepared by a known method, or the transition metal complex can be usedwith generating it in the coupling reaction system by adding atransition metal salt and a ligand separately. Examples thereof includea combination of nickel chloride and triphenylphosphine, a combinationof nickel bromide and triphenylphosphine, a combination of nickelacetate and triphenylphosphine, a combination of palladium chloride andtriphenylphosphine, a combination of palladium bromide andtriphenylphosphine, a combination of palladium acetate andtriphenylphosphine, a combination of nickel chloride and1,2-bis(diphenylphosphino)ethane, a combination of nickel bromide and1,2-bis(diphenylphosphino)ethane, a combination of nickel acetate and1,2-bis(diphenylphosphino)ethane, a combination of palladium chlorideand 1,2-bis(diphenylphosphino)ethane, a combination of palladium bromideand 1,2-bis(diphenylphosphino)ethane, a combination of palladium acetateand 1,2-bis(diphenylphosphino)ethane, a combination of nickel chlorideand 1,3-bis(diphenylphosphino)propane, a combination of nickel bromideand 1,3-bis(diphenylphosphino)propane, a combination of nickel acetateand 1,3-bis(diphenylphosphino)propane, a combination of palladiumchloride and 1,3-bis(diphenylphosphino)propane, a combination ofpalladium bromide and 1,3-bis(diphenylphosphino)propane, a combinationof palladium acetate and 1,3-bis(diphenylphosphino)propane, and thelike.

The reaction in the production of compound (II) from compound (I) iscarried out without solvent or with making a dilution in solvent.Examples of the reaction solvent include hydrocarbon solvents such aspetroleum ether, pentane, hexane, cyclohexane, benzene, toluene, xyleneetc., halogenated hydrocarbon solvents such as dichloromethane,1,2-dichloroethane, chloroform, carbon tetrachloride, trichloroethane,trichloroethylene, tetrachloroethane, chlorobenzene, etc., ethersolvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran(abbreviation: THF), 1,4-dioxane, dimethoxyethane (abbreviation: DME),diethylene glycol dimethyl ether, etc., ketone solvents such as acetone,methyl ethyl ketone, 2-pentanone, 3-pentanone, cyclohexanone, etc.,ester solvents such as ethyl acetate, butyl acetate, etc., amidesolvents such as N,N-dimethylformamide (abbreviation: DMF),N,N-dimethylacetamide, N-methylpyrrolidone, etc., nitrile solvents suchas acetonitrile, propionitrile, etc., solvents containing sulfur such asdimethyl sulfoxide, dimethyl sulfone, solfolane, carbon disulfide, etc.,nitro compound solvents such as nitromethane, nitrobenzene, etc., proticsolvents such as water, methanol, ethanol, propanol, isopropanol,t-butanol, ethylene glycol, phenol, acetic acid, etc. As a preferablesolvent, hydrocarbon solvents or ether solvents are exemplified. Thesesolvents are usually used alone, or may be used with mixing in anappropriate ratio.

The reaction temperature is −100° C. to 300° C., preferably −50° C. to100° C., and more preferably −20° C. to 50° C.

The reaction time is 10 seconds to 500 hours, preferably 1 minute to 48hours, and more preferably 10 minutes to 24 hours.

The ratio of the organometallic compound used to compound (I) is 0.5 to10 equivalents, preferably 0.8 to 3.0 equivalents, and particularlypreferably 1.0 to 1.5 equivalents.

The ratio of the transition metal catalyst used to compound (I) is0.000001 to 10 equivalents, preferably 0.00001 to 1 equivalent, andparticularly preferably 0.0001 to 0.1 equivalent.

The method which leads compound (IIa) to a sulfonamide represented bythe formula (III) by sulfonating compound (IIa) with chlorosulfonicacid, followed by converting to sulfonyl chloride with phosphorylchloride, and then reacting with ammonia, can be carried out accordingto a similar method to the known art (JP-B H05-36439).

The method which leads compound (IIb) to a sulfonamide represented bythe formula (III) by hydrolyzing compound (IIb) can be carried outaccording to a similar method to the known art (Protective Groups inOrganic Synthesis, page 275).

The reaction of the present invention has a feature that the substituentZ of 6-position is selectively substituted even when the substituent Xof 2-position of imidazo[1,2-b]pyridazine ring is a halogen atom such aschlorine atom etc. Furthermore, the reaction of the present inventionhas a feature that the reaction proceeds without amide polar solventssuch as HMPT (hexamethylphosphoric triamide) and DMA (dimethylacetamide)used in the prior art, which is suspected of toxicity. In addition, thereaction of the present invention proceeds at ice-cooling to roomtemperature in most cases with the exception of using palladium catalystin toluene solvent, and heating such as disclosed in prior arts is notrequired.

EXAMPLES

Hereinafter, this invention will be further illustrated by Examples andReference Examples, but this invention is not limited thereto. Theelution in silica gel column chromatography was carried out under theobservation by TLC (Thin Layer Chromatograph). In the observation byTLC, kieselgel 60F254 (70 to 230 mesh) manufactured by Merck was used asTLC plate, the solvent used as an eluting solvent in columnchromatography was used as developing solvent, and a UV detector oriodine color-developing method was used for detection. As silica gel forcolumn, kieselgel 60 (70 to 230 mesh) manufactured by Merck was used. Incase that a mixed solvent was used as developing solvent, the numericvalue shown in parentheses indicates volumetric mixing ratio of eachsolvents. NMR (nuclear magnetic resonance) spectra show proton NMR, andwere determined with Bruker AV-400 (400 MHz) spectrometer withtetramethylsilane as internal standard, and all delta values are shownin ppm. The abbreviations used in the following Reference Examples andExamples have the following meanings.

s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, dd: doubledoublet, dt: double triplet, dq: double quartet, sept: septet, br:broad, brs: broad singlet, ddd: double double doublet, ddt: doubledouble triplet, brd: broad doublet, brq: broad quartet, J: couplingconstant, Hz: Hertz, Me: methyl group, Et: ethyl group, Pr: propylgroup, i-Pr: isopropyl group, c-Pr: cyclopropyl group, Bu: butyl group,i-Bu: isobutyl group, dppp: 1,3-bis(diphenylphosphino)propane, PPh₃:triphenylphosphine, CDCl₃: heavy chloroform, DMSO-d₆: heavy dimethylsulfoxide, DMF: N,N-dimethylformamide, HPLC: high performance liquidchromatography, %: weight %, mp: melting point, and room temperaturemeans a temperature of 15 to 25° C.

Example 1 Synthesis of 6-ethyl-2-methylimidazo[1,2-b]pyridazine

6-Chloro-2-methylimidazo[1,2-b]pyridazine (5.00 g, 29.8 mmol) and[1,3-bis(diphenylphosphino)propane]nickel(II) dichloride (0.08 g, 0.15mmol) were suspended in dry ether (40 ml)-dry THF (20 ml), and asolution of ethylmagnesium bromide in ether (3 M, 15 ml, 45 mmol) wasadded dropwise thereto with stirring under ice-cooling over 5 minutes(internal temperature 10° C. or less). The temperature of the reactionsolution was increased to room temperature, and the mixture was stirredat the same temperature for 2 hours and under reflux with heating for 3hours. The reaction solution was left to cool to room temperature understirring, and water (30 ml) was added little by little. Further, the pHof reaction mixture was adjusted to about 5 to 6 with concentratedhydrochloric acid under stirring at room temperature. The organic layerand the aqueous layer were separated from each other, and the aqueouslayer was extracted with ethyl acetate (70 ml×2). The organic layerswere combined and washed with water (250 ml×3). The organic layer wasdried over magnesium sulfate and concentrated, and the residues werepurified by silica gel column chromatography (chloroform:ethylacetate=2:1→1:1), and the resulting crude oil was further purified bysilica gel column chromatography (ethyl acetate), and the title compoundwas obtained as pale red oil. The yield was 1.32 g (27.4%).

¹H NMR (CDCl₃, δ): 1.33 (3H, t, J=7.5 Hz), 2.48 (3H, s), 2.82 (2H, q,J=7.5 Hz), 6.87 (1H, d, J=9.2 Hz), 7.65 (1H, s), 7.72 (1H, d, J=9.2 Hz)

IR (Neat, cm⁻¹): 2973, 2934, 2876, 1543, 1460, 1382, 1333, 1300, 1263,1155, 1125, 1057, 1000, 820, 726, 699

Example 2 Synthesis of6-ethyl-2-methylimidazo[1,2-b]pyridazin-3-sulfonamide

6-Ethyl-2-methylimidazo[1,2-b]pyridazine (2.70 g, 16.7 mmol) wasdissolved in 1,2-dichloroethane (30 ml), and chlorosulfonic acid (1.27g, 18.5 mmol) was added thereto under stirring at room temperature, andthe mixture was stirred for 5 hours under reflux with heating. Then, thereaction solution was cooled to about 70° C., and triethylamine (2.38 g,23.5 mmol) was added dropwise thereto over 1 minute. After dropping, thereaction solution was stirred for 20 minutes under reflux with heating.Thereafter, the reaction solution was cooled to about 70° C., andphosphorus oxychloride (3.86 g, 25.2 mmol) was added dropwise theretoover 1 minute. After dropping, the mixture was stirred for 2 hours underreflux with heating. The reaction solution was left to cool to about 50°C., and poured into 50 ml warm water (about 50° C.). The reactionmixture was stirred for 5 minutes, and the organic layer was separated.The aqueous layer was extracted with chloroform (50 ml×2). The organiclayers were combined, washed with water, dried over magnesium sulfate,and concentrated. The residues were dissolved in acetonitrile (40 ml),and 14 N ammonia water (7 ml) was added thereto under stirring at roomtemperature, and the mixture was stirred at room temperature for 2hours. After the reaction was completed, the reaction solution waspoured onto ice-cold water (150 ml) and adjusted to about pH 4 withconcentrated hydrochloric acid, to form crystals which were thencollected by filtration, washed with water and dried under reducedpressure. Thereafter, the crystals were purified by silica gel columnchromatography (chloroform:acetone=9:1→4:1). The title compound wasobtained as white crystals. The yield was 1.8 g (44.7%).

mp 215.0-215.5° C.

¹H NMR (DMSO-d₆, δ): 1.30 (3H, t, J=7.5 Hz), 2.57 (3H, s), 2.93 (2H, q,J=7.5 Hz), 7.39 (1H, d, J=9.3 Hz), 7.47 (2H, brs), 8.08 (1H, d, J=9.3Hz)

IR (Nujol, cm⁻¹): 3304, 3177, 3090, 1546, 1540, 1507, 1463, 1389, 1362,1341, 1309, 1201, 1166, 1127, 1086, 1057, 959, 900, 9864, 824, 772, 686,670, 652, 591, 525

Example 3 Synthesis of 2-chloro-6-n-propylimidazo[1,2-b]pyridazine

2,6-Dichloroimidazo[1,2-b]pyridazine (10.0 g, 53.2 mmol) and[1,3-bis(diphenylphosphino)propane]nickel(II) dichloride (0.43 g, 0.80mmol) were added to tetrahydrofuran (80.0 ml) under a nitrogen stream,and a solution of n-propylmagnesium bromide in tetrahydrofuran (2 M,31.9 ml, 63.8 mmol) was added dropwise thereto under ice-cooling over 60minutes. The reaction mixture was stirred for 10 minutes underice-cooling, warmed to room temperature, and stirred for 2 hours at roomtemperature. To the reaction mixture was added cold water (700 ml), andacidified with concentrated hydrochloric acid. Then the deposited solidwas collected by filtration, and insoluble solid was washed with dilutehydrochloric acid, then with water. At the same time, the filtrate wasextracted with ethyl acetate, the extracts were combined, and washedwith dilute hydrochloric acid, saturated brine, saturated sodiumhydrogen carbonate solution, and saturated brine, in that order. Theresulting organic layer was dried over anhydrous magnesium sulfate,filtered, and concentrated. The concentrated residue and the solidcollected by filtration were purified by silica gel columnchromatography (ethyl acetate:hexane=3:7) to give the title compound aswhite crystals. The yield was 9.21 g (88.5%).

mp: 73.9-80.0° C.

¹H NMR (CDCl₃, δ): 1.01 (3H, t, J=7.4 Hz), 1.78 (2H, m), 2.79 (2H, t,J=7.6 Hz), 6.96 (1H, d, J=9.3 Hz), 7.75 (1H, d, J=9.3 Hz), 7.80 (1H, s).

IR (Nujol, cm⁻¹): 3122, 1466, 1377, 1314, 1302.

Example 4 Synthesis of2-chloro-6-n-propylimidazo[1,2-b]pyridazin-3-sulfonamide

2-Chloro-6-n-propylimidazo[1,2-b]pyridazine (0.8 g, 4.1 mmol) anddichloroethane (10 ml) were introduced into a 200-ml eggplant type flaskand stirred at room temperature, and chlorosulfonic acid (0.54 g, 4.5mmol) was added thereto all at once, and the mixture was stirred for 4hours under reflux with heating. The reaction solution was cooled toabout 70° C., and triethylamine (0.5 g, 5 mmol) was added thereto all atonce and stirred until the solid was dissolved, and phosphorusoxychloride (0.79 g, 5 mmol) was added thereto all at once, and themixture was stirred for 2 hours under reflux with heating. After thereaction was completed, the reaction solution was left to cool, andwater (50 ml) was added thereto and the organic phase was separated. Theorganic phase was washed with a saturated saline, dried over magnesiumsulfate and concentrated. Acetonitrile (10 ml) and 28% ammonia water (4ml) were added to the residue and stirred at room temperature for 2hours. After the reaction was completed, water (100 ml) was added to thereaction solution, which was then adjusted to about pH 2 with dilutehydrochloric acid, and the formed crystals were collected by filtration,washed with water and chloroform, and dried under reduced pressure togive the title compound as pale brown crystals. The yield was 0.49 g(43.5%).

mp 174-5° C.

¹H NMR (DMSO-d₆, δ): 0.96 (3H, t, J=7.4 Hz), 1.7-1.9 (2H, m), 2.8-3.0(2H, m), 7.53 (1H, d, J=9.5 Hz), 7.82 (2H, brs), 8.19 (1H, d, J=9.4 Hz)

IR (Nujol, cm⁻¹): 3377, 3324, 3189, 1545, 1364, 1322, 1187, 1166, 821,680, 597

Example 5 Synthesis of 6-n-butyl-2-chloroimidazo[1,2-b]pyridazine

Zinc chloride (2.04 g, 15.0 mmol) was dried at 180° C. for 2 hours undervacuum and then cooled to room temperature, and anhydroustetrahydrofuran (20.0 mL) was added thereto. n-Butyl lithium (1.6 M, 9.0mL, 14.4 mmol) was added dropwise thereto over about 30 minutes underice-cooling and stirred for 30 minutes under ice-cooling, to prepare asolution of n-butylzinc chloride in tetrahydrofuran. Separately, asuspension of 2,6-dichloroimidazo[1,2-b]pyridazine (1.88 g, 10.0 mmol)and [1,3-bis(diphenylphosphino)propane]nickel(II) dichloride (0.16 g,0.30 mmol) in anhydrous tetrahydrofuran (20.0 mL) was prepared under anitrogen atmosphere, and the previously prepared solution of n-butylzincchloride in tetrahydrofuran was added dropwise thereto over 30 minuteswith maintaining at 3 to 6° C. The mixture was stirred for 15 minutesunder ice-cooling and for 3 hours at room temperature, poured into asaturated saline and adjusted to pH 2 with dilute hydrochloric acid. Thereaction solution was extracted twice with ethyl acetate, and theextracts were combined, dehydrated over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residues were purified bysilica gel column chromatography (ethyl acetate:hexane=1:4) to give thetitle compound as pale yellow crystals. The yield was 2.03 g (96.8%).

mp 61.0-63.0° C.

¹H NMR (CDCl₃, δ): 0.96 (3H, t, J=7.3 Hz),1.41 (2H, tq, J=7.5, 7.3 Hz),1.73 (2H, tt, J=7.8, 7.5 Hz), 2.81 (2H, t, J=7.8 Hz), 6.96 (1H, d, J=9.4Hz), 7.74 (1H, d, J=9.4 Hz), 7.79 (1H, s).

IR (Nujol, cm⁻¹): 3115, 3061, 1545, 1466, 1378, 1326, 1276, 817.

Example 6 Synthesis of6-n-butyl-2-chloroimidazo[1,2-b]pyridazin-3-ylsulfonamide

6-n-Butyl-2-chloroimidazo[1,2-b]pyridazine (1.00 g, 4.77 mmol) wasdissolved in chloroform (10.0 mL), and chlorosulfonic acid (0.35 mL,5.27 mmol) was added dropwise to the solution under stirring at roomtemperature. After the mixture was heated for 5 hours under reflux, itwas confirmed by TLC that the starting material remained, so additionalchlorosulfonic acid (0.35 mL, 5.27 mmol) was added thereto, and themixture was heated for 4 hours under reflux. The resulting suspensionwas left to cool to room temperature, and triethylamine (2.50 mL, 17.9mmol) and phosphorus oxychloride (2.00 mL, 21.5 mmol) were addedthereto, and the mixture was heated again for 4 hours under reflux. Thereaction solution was cooled to room temperature, poured into water andextracted 3 times with chloroform, and the extracts were combined,dehydrated over anhydrous magnesium sulfate and concentrated underreduced pressure to give 3.24 g dark red liquid. This liquid wasdissolved in acetonitrile (10.0 mL) and added dropwise to a solution of25% ammonia water (5.00 g, 73.5 mmol) in acetonitrile (15.0 mL) underice-cooling. The mixture was stirred for 30 minutes under ice-coolingand for 1 hour at room temperature, and then the acetonitrile wasdistilled away under reduced pressure. The residues were adjusted to pH2 with dilute hydrochloric acid and extracted twice with chloroform, andthe chloroform layers were combined, dehydrated over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residues werepurified by silica gel column chromatography (ethylacetate:hexane=1:1→chloroform:ethanol=20:1) to give the title compoundas white crystals. The yield was 0.92 g (66.8%).

mp 165.5-166.5° C.

¹H NMR (DMSO-d₆, δ): 0.93 (3H, t, J=7.3 Hz), 1.37 (2H, tq, J=7.5, 7.3Hz), 1.72 (2H, tt, J=7.9, 7.5 Hz), 2.93 (2H, t, J=7.9 Hz), 7.53 (1H, d,J=9.4 Hz), 7.80 (2H, s), 8.18 (1H, d, J=9.4 Hz).

IR (Nujol, cm⁻¹): 3412, 3360, 3287, 3197, 1546, 1464, 1376, 1321, 1172.

Example 7 Synthesis ofN′-(2-chloro-6-cyclopropylimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine

Magnesium metal powder (0.27 g, 11.1 mmol) was mixed with iodine (5 mg),heated with a dryer under a nitrogen atmosphere and cooled to roomtemperature, and anhydrous tetrahydrofuran (15.0 mL) was added thereto.Cyclopropyl bromide (1.33 g, 1.10 mmol), while keeping at 28 to 33° C.,was added dropwise to the mixture under stirring at room temperature,and then the mixture was stirred at room temperature for 30 minutes toprepare a pale yellowish gray solution of cyclopropylmagnesium bromidein tetrahydrofuran. Separately, zinc chloride (1.50 g, 11.0 mmol) driedat 180° C. for 4 hours under vacuum was dissolved in anhydroustetrahydrofuran (10.0 mL) under a nitrogen atmosphere and then thepreviously prepared solution of cyclopropylmagnesium bromide intetrahydrofuran was added dropwise thereto with keeping at 0° C. or lesswith an ice-sodium chloride bath. The mixture was stirred at about −10°C. for 15 minutes, and [1,3-bis(diphenylphosphino)propane]nickel(II)dichloride (0.27 g, 0.50 mmol) was added as powder to the resultingsuspension, and then a solution ofN′-(2,6-dichloroimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine(2.03 g, 5.00 mmol) dissolved in anhydrous tetrahydrofuran (10.0 mL) wasadded dropwise thereto. The mixture was stirred at −10° C. for 2 hours,then at room temperature for 16 hours, poured into a saturated saline,adjusted to pH 2 with dilute hydrochloric acid, and extracted 4 timeswith chloroform. The extracts were combined, dehydrated over anhydrousmagnesium sulfate, concentrated under reduced pressure, and the residueswere purified by silica gel column chromatography (ethylacetate:hexane=1:1), whereby 0.64 g (31.5%) of the starting materialN′-(2,6-dichloroimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidinewas recovered and simultaneously the title compound was obtained as paleyellow crystals. The yield was 0.94 g (45.7%).

mp 154.0-160.0° C.

¹H NMR (CDCl₃, δ): 0.74 (6H, d, J=6.7 Hz), 0.95 (6H, d, J=6.7 Hz),1.00-1.10 (2H, m), 1.10-1.25 (2H, m), 1.85-2.10 (2H, m), 2.10-2.20 (1H,m), 3.19 (2H, d, J=7.5 Hz), 3.28 (2H, d, J=7.5 Hz), 6.98 (1H, d, J=9.4Hz), 7.78 (1H, d, J=9.4 Hz), 8.45 (1H, s).

IR (Nujol) ν (cm⁻¹): 1613, 1464, 1334, 1318, 1143, 909, 859, 661.

Example 8 Synthesis of2-chloro-6-cyclopropylimidazo[1,2-b]pyridazin-3-ylsulfonamide

N′-(2-Chloro-6-cyclopropylimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine(0.93 g, 2.26 mmol) was dissolved in dioxane (9.00 mL), and 36%concentrated hydrochloric acid (9.0 mL, 107 mmol) was added dropwise tothe solution under stirring at 100° C. The mixture was stirred for 15hours at 100 to 105° C., then left to cool to room temperature andconcentrated under reduced pressure until crystals occurred. Water (30.0mL) was poured into the residues, and the crystals were completelyprecipitated, then filtered, washed with water and washed with methanol,to give the title compound as white crystals. The yield was 0.31 g(50.4%).

mp 194.0-196.0° C.

NMR (DMSO-d₆, δ): 1.10-1.25 (4H, m), 2.30-2.45 (1H, m), 7.36 (1H, d,J=9.4 Hz), 7.78 (2H, brs), 8.12 (1H, d, J=9.4 Hz).

IR (Nujol, cm⁻¹): 3348, 3247, 1553, 1468, 1455, 1358, 1316, 1170, 908,825, 662.

Example 9 Synthesis ofN′-(2-chloro-6-ethenylimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine

The title compound was obtained as pale yellow crystals by the samereaction as in Example 7 except that a solution of commerciallyavailable vinyl magnesium bromide in tetrahydrofuran was used in placeof the solution of cyclopropylmagnesium bromide in tetrahydrofuran, and[1,3-bis(diphenylphosphino)propane]nickel(II) dichloride was used in anamount of 3 mol-% relative to the starting materialN′-(2,6-dichloroimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine.The yield was 80.4%.

mp 194.0-198.0° C.

¹H NMR (CDCl₃, δ): 0.71 (6H, d, J=6.7 Hz), 0.94 (6H, d, J=6.6 Hz),1.85-2.10 (2H, m), 3.17 (2H, d, J=7.5 Hz), 3.26 (2H, d, J=7.7 Hz), 5.77(1H, d, J=11.1 Hz), 6.16 (1H, d, J=17.8 Hz), 6.82 (1H, dd, J=17.8, 11.1Hz), 7.46 (1H, d, J=9.5 Hz), 7.89 (1H, d, J=9.5 Hz), 8.50 (1H, s).

IR (Nujol, cm⁻¹): 1614, 1456, 1350, 1319, 1145, 913, 859, 664, 612.

Example 10 Synthesis of2-chloro-6-ethenylimidazo[1,2-b]pyridazin-3-ylsulfonamide

The reaction was carried out in the same manner as in Example 8 exceptthatN′-(2-chloro-6-ethenylimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidinewas used in place ofN′-(2-chloro-6-cyclopropylimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine.The resulting crystals were purified by silica gel column chromatography(chloroform:methanol=10:1) to give the title compound as white crystals.The yield was 42.1%.

mp 229.0-233.0° C.

¹H NMR (DMSO-d₆, δ): 5.87 (1H, d, J=11.2 Hz), 6.50 (1H, d, J=17.9 Hz),6.86 (1H, dd, J=17.9, 11.2 Hz), 7.89 (2H, s), 7.96 (1H, d, J=9.6 Hz),8.26 (1H, d, J=9.6 Hz).

IR (Nujol, cm⁻¹): 3316, 3183, 1466, 1368, 1321, 1167.

Example 11 Synthesis ofN′-(2-chloro-6-(1-propenyl)imidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine

The title compound was obtained as a mixture of E and Z (E:Z=5:3) in theform of pale yellow crystals by the same reaction as in Example 7 exceptthat a solution of commercially available 1-propenylmagnesium bromide intetrahydrofuran was used in place of the solution ofcyclopropylmagnesium bromide in tetrahydrofuran, and[1,3-bis(diphenylphosphino)propane]nickel(II) dichloride was used in anamount of 3 mol-% relative to the starting materialN′-(2,6-dichloroimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine.The yield was 100%. mp: not be measured because of a mixture of E and Z.

¹H NMR (CDCl₃, δ): [E isomer] 0.72 (6H, d, J=6.6 Hz), 0.94 (6H, d, J=6.6Hz), 1.85-2.10 (2H, m), 2.00 (3H, dd, J=6.9, 1.5 Hz), 3.17 (2H, d, J=7.6Hz), 3.26 (2H, d, J=7.7 Hz), 6.51 (1H, dq, J=16.0, 1.5 Hz), 6.71 (1H,dq, J=16.0, 6.9 Hz), 7.35 (1H, d, J=9.5 Hz), 7.82 (1H, d, J=9.5 Hz),8.50 (1H, s).

¹H NMR (CDCl₃, δ): [Z isomer] 0.72 (6H, d, J=6.6 Hz), 0.92 (6H, d, J=6.6Hz), 1.85-2.10 (2H, m), 2.21 (3H, dd, J=7.3, 1.8 Hz), 3.12 (2H, d, J=7.5Hz), 3.25 (2H, d, J=7.7 Hz), 6.23 (1H, dq, J=11.9, 7.3 Hz), 6.40 (1H,dq, J=11.9, 1.8 Hz), 7.19 (1H, d, J=9.5 Hz), 7.85 (1H, d, J=9.5 Hz),8.43 (1H, s).

IR (Nujol, cm⁻¹): 1609, 1456, 1351, 1319, 1144, 911.

Example 12 Synthesis of(E)-2-chloro-6-(1-propenyl)imidazo[1,2-b]pyridazin-3-ylsulfonamide

The reaction was carried out in the same manner as in Example 8 exceptthatN′-(2-chloro-6-(1-propenyl)imidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidineas a mixture of E and Z was used in place ofN′-(2-chloro-6-cyclopropylimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine.The resulting crystals were purified by silica gel column chromatography(chloroform:methanol=20:1) to give the title compound as white crystals.The yield was 70.1%.

mp 225.0-229.0° C.

¹H NMR (DMSO-d₆, δ): 1.98 (3H, dd, J=6.8, 1.7 Hz), 6.71 (1H, dq, J=16.0,1.7 Hz), 7.01 (1H, dq, J=16.0, 6.8 Hz), 7.83 (2H, s), 7.84 (1H, d, J=9.5Hz), 8.19 (1H, d, J=9.6 Hz).

IR (Nujol, cm⁻¹): 3323, 3179, 1662, 1550, 1466, 1360, 1325, 1173.

Example 13 Synthesis of 2-chloro-6-isobutylimidazo[1,2-b]pyridazine

The reaction was carried out in the same manner as in Example 3 exceptthat a solution of isobutylmagnesium bromide in tetrahydrofuran was usedin place of the solution of n-propylmagnesium bromide intetrahydrofuran. The resulting crude product was purified by silica gelcolumn chromatography (ethyl acetate:hexane=1:4) to give the titlecompound as pale yellow crystals. The yield was 1.27 g (60.6%).

mp 71.0-72.5° C.

¹H NMR (CDCl₃, δ): 0.98 (6H, d, J=6.6 Hz), 2.09 (1H, m), 2.68 (2H, d,J=7.3 Hz), 6.94 (1H, d, J=9.3 Hz), 7.75 (1H, d, J=9.3 Hz), 7.81 (1H,s).

IR (Nujol, cm⁻¹): 3126, 3059, 1545, 1466, 1369, 1331, 1320, 1279, 803.

Example 14 Synthesis of2-chloro-6-isobutylimidazo[1,2-b]pyridazin-3-ylsulfonamide

The reaction was carried out in the same manner as in Example 6 exceptthat 2-chloro-6-isobutylimidazo[1,2-b]pyridazine was used in place of2-chloro-6-n-butylimidazo[1,2-b]pyridazine. The resulting reactionmixture was purified by silica gel column chromatography (ethylacetate:hexane=1:1) to give the title compound as white crystals. Theyield was 1.12 g (64.0%).

mp 168.0-169.5° C.

¹H NMR (DMSO-d₆, δ): 0.93 (6H, d, J=6.6 Hz), 2.14 (1H, m), 2.82 (2H, d,J=7.4 Hz), 7.51 (1H, d, J=9.4 Hz), 7.80 (2H, s), 8.19 (1H, d, J=9.4 Hz).

IR (Nujol, cm⁻¹): 3316, 3180, 3117, 1548, 1469, 1362, 1336, 1321, 1200,1173, 849, 678.

Example 15 Synthesis of 2-chloro-6-ethylimidazo[1,2-b]pyridazine

The title compound was obtained as pale yellow crystals by the samereaction as in Example 3 except that a solution of ethylmagnesiumchloride in tetrahydrofuran was used in place of the solution ofn-propylmagnesium bromide in tetrahydrofuran. The yield was 66.2%.

¹H NMR (CDCl₃, δ): 1.35 (3H, t, J=7.6 Hz), 2.85 (2H, q, J=7.6 Hz), 6.97(1H, d, J=9.3 Hz), 7.75 (1H, d, J=9.3 Hz), 7.80 (1H, s).

IR (Nujol, cm¹): 3121, 3058, 1544, 1471, 1318, 1280, 1262, 1189, 1142,1121, 1059, 983, 953, 822.

Example 16 Synthesis of2-chloro-6-ethylimidazo[1,2-b]pyridazin-3-ylsulfonamide

The title compound was obtained as pale brown crystals by the samereaction as in Example 4 except that2-chloro-6-ethylimidazo[1,2-b]pyridazine was used in place of2-chloro-6-n-propylimidazo[1,2-b]pyridazine. The yield was 74.1%.

mp 204-205° C.

¹H NMR (DMSO-d₆, δ): 1.31 (3H, t, J=7.6 Hz), 2.95 (2H, q, J=7.6 Hz),7.54 (1H, d, J=9.4 Hz), 7.82 (2H, brs), 8.19 (1H, d, J=9.4 Hz).

IR (Nujol, cm⁻¹): 3317, 3211, 1365, 1356, 1325, 1172, 829, 668.

Example 17 Synthesis of 2-methyl-6-n-propylimidazo[1,2-b]pyridazine

The title compound was obtained as pale reddish oil by the same reactionas in Example 1 except that a solution of n-propylmagnesium chloride inether was used in place of the solution of ethylmagnesium bromide inether, and as the solvent, a tetrahydrofuran solvent was used in placeof the mixed solvent of ether and tetrahydrofuran. The yield was 19.1%.

¹H NMR (CDCl₃, δ): 1.00 (3H, t, J=7.4 Hz), 1.7-1.9 (2H, m), 2.48 (3H, d,J=0.7 Hz), 2.77 (2H, t, J=7.5 Hz), 6.85 (1H, d, J=9.2 Hz), 7.66 (1H, d,J=0.7 Hz), 7.72 (1H, d, J=9.2 Hz).

IR (Nujol, cm⁻¹): 2961, 1541, 1464, 1326, 1296, 1153, 1124, 989, 816,726.

Example 18 Synthesis of2-methyl-6-n-propylimidazo[1,2-b]pyridazin-3-ylsulfonamide

The title compound was obtained as pale brown crystals by the samereaction as in Example 4 except that2-methyl-6-n-propylimidazo[1,2-b]pyridazine was used in place of2-chloro-6-n-propylimidazo[1,2-b]pyridazine. The yield was 14.6%.

mp 178-179° C. (dec.)

¹H NMR (DMSO-d₆, δ): 0.96 (3H, t, J=7.3 Hz), 1.7-1.9 (2H, m), 2.56 (3H,s), 2.8-2.9 (2H, m), 7.39 (1H, d, J=9.3 Hz), 7.46 (2H, brs), 8.08 (1H,d, J=9.3 Hz).

IR (Nujol, cm¹): 3384, 3327, 1543, 1508, 1420, 1348, 1327, 1309, 1162,827.

Example 19 Synthesis ofN,N-dimethyl-N′-(6-n-propyl-2-trifluoromethylimidazo[1,2-b]pyridazin-3-ylsulfonyl)formamidine

To a suspension ofN′-(6-chloro-2-trifluoromethylimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-dimethylformamidine(1.00 g, 2.81 mmol) and [1,3-bis(diphenylphosphino)propane]nickel(II)dichloride (0.076 g, 0.14 mmol) in tetrahydrofuran (8.0 ml) was addeddropwise a solution of n-propylzinc bromide in tetrahydrofuran (0.5 M,8.43 ml, 4.22 mmol) with stirring under ice-cooling and nitrogen stream.The reaction mixture was stirred for 30 minutes under ice-cooling and4.5 hours at room temperature, then poured into cold water and made acidwith dilute hydrochloric acid. The precipitated solid was collected byfiltration, washed with dilute hydrochloric acid, then water, andpurified by silica gel column chromatography (ethylacetate:chloroform=2:5) to give the title compound as white crystals.The yield was 0.62 g (60.7%).

mp 219.3-220.4° C.

¹H NMR (DMSO-d₆, δ): 0.95 (3H, t, J=7.3 Hz), 1.71 (2H, m), 2.88 (2H, t,J=7.7 Hz), 2.92 (3H, s), 3.28 (3H, s), 7.59 (1H, d, J=9.5 Hz), 8.33 (1H,d, J=9.5 Hz), 8.54 (1H, s).

IR (Nujol, cm⁻¹): 1635, 1334, 1318, 1169, 1153, 920, 619.

Example 20 Synthesis of6-n-propyl-2-trifluoromethylimidazo[1,2-b]pyridazin-3-ylsulfonamide

N,N-dimethyl-N′-(6-n-propyl-2-trifluoromethylimidazo[1,2-b]pyridazin-3-ylsulfonyl)formamidine(0.30 g, 0.83 mmol) was dissolved in dioxane (10.0 ml), and to thesolution was added concentrated hydrochloric acid (5.0 ml) and stirredat 60° C. for 2 hours, 80° C. for 2 hours and 90° C. for 2 hours. Thereaction mixture was concentrated under reduced pressure. To theresidues was added water, and adjusted pH to 3 with aqueous 1N sodiumhydroxide solution. The precipitated solid was collected by filtration,and washed with water to give the title compound as white crystals. Theyield was 0.24 g (94.3%).

mp 151.0-151.7° C.

¹H NMR (DMSO-d₆, δ): 0.97 (3H, t, J=7.3 Hz), 1.78 (2H, m), 2.96 (2H, t,J=7.7 Hz), 7.62 (1H, d, J=9.5 Hz), 7.97 (2H, brs), 8.36 (1H, d, J=9.5Hz).

IR (Nujol, cm⁻¹): 3356, 1550, 1465, 1373, 1362, 1322, 1199, 1179, 1151,608.

Example 21 Synthesis of 2-chloro-6-n-propylimidazo[1,2-b]pyridazine

2,6-Dichloroimidazo[1,2-b]pyridazine (0.50 g, 2.66 mmol) andbis(triphenylphosphine)nickel(II) dichloride (0.17 g, 0.27 mmol) wereadded to tetrahydrofuran (5.0 ml) under a nitrogen stream, and asolution of n-propylmagnesium bromide in tetrahydrofuran (2 M, 1.99 ml,3.99 mmol) was added dropwise over 10 minutes to the mixture underice-cooling. The mixture was stirred for 10 minutes under ice-cooling,and the reaction mixture was warmed to room temperature and stirred for4 hours at room temperature. Cold water (50 ml) was added to thereaction mixture which was then acidified with dilute hydrochloric acid,and extracted with ethyl acetate. The extracts were washed with dilutehydrochloric acid, a saturated saline, an aqueous saturated sodiumbicarbonate solution and a saturated saline in this order. The resultingorganic layer was dried over anhydrous magnesium sulfate, filtrated andconcentrated. The concentrated residue was purified by silica gel columnchromatography (ethyl acetate:hexane=3:7) to give the title compound aswhite crystals. The yield was 0.21 g (40.4%).

Example 22 Synthesis of 2-chloro-6-n-propylimidazo[1,2-b]pyridazine

Under a nitrogen stream, a solution of n-propylzinc bromide intetrahydrofuran (0.5 M, 7.98 ml, 3.99 mmol) was diluted with toluene(5.0 ml), and 2,6-dichloroimidazo[1,2-b]pyridazine (0.50 g, 2.66 mmol)and bis(triphenylphosphine)palladium(II) dichloride (0.19 g, 0.27 mmol)were added thereto, and the reaction mixture was stirred for 2 hours at80° C. After cooling, to the reaction mixture was added cold water (50ml), acidified with dilute hydrochloric acid, extracted with ethylacetate, and the extracts were washed with dilute hydrochloric acid, asaturated saline, an aqueous saturated sodium bicarbonate solution and asaturated saline in this order. The resulting organic layer was driedover anhydrous magnesium sulfate, filtrated and concentrated. Theconcentrated residue was purified by silica gel column chromatography(ethyl acetate:hexane=3:7) to give the title compound as white crystals.The yield was 0.31 g (59.6%).

Example 23 Synthesis of 2-chloro-6-n-propylimidazo[1,2-b]pyridazine

Under a nitrogen stream, 2,6-dichloroimidazo[1,2-b]pyridazine (1.00 g,5.32 mmol), bis(triphenylphosphine)nickel(II) dichloride (0.10 g, 0.16mmol) and zinc bromide (0.04 g, 0.16 mmol) were added to tetrahydrofuran(8.0 ml), and a solution of n-propylmagnesium bromide in tetrahydrofuran(2 M, 3.99 ml, 7.98 mmol) was added dropwise over 10 minutes to themixture under ice-cooling. The reaction mixture was stirred for 10minutes under ice-cooling, and warmed to room temperature and stirredfor 4 hours at room temperature. Cold water (100 ml) was added to thereaction mixture which was then acidified with dilute hydrochloric acid,and extracted with ethyl acetate. The extracts were washed with dilutehydrochloric acid, a saturated saline, an aqueous saturated sodiumbicarbonate solution and a saturated saline in this order. The resultingorganic layer was dried over anhydrous magnesium sulfate, filtrated andconcentrated. The concentrated residue was purified by silica gel columnchromatography (ethyl acetate:hexane=3:7) to give the title compound aspale yellow crystals. The yield was 0.76 g (73.1%).

Example 24 Synthesis of 2-chloro-6-n-propylimidazo[1,2-b]pyridazine

Under a nitrogen stream, 2,6-dichloroimidazo[1,2-b]pyridazine (0.50 g,2.66 mmol) and bis(triphenylphosphine)nickel(II) dichloride (0.17 g,0.27 mmol) were added to tetrahydrofuran (5.0 ml), and a solution ofn-propylzinc bromide in tetrahydrofuran (0.5 M, 7.98 ml, 3.99 mmol) wasadded dropwise over 10 minutes to the mixture under ice-cooling. Thereaction mixture was stirred for 10 minutes under ice-cooling, andwarmed to room temperature and stirred for 2 hours at room temperature.Cold water (50 ml) was added to the reaction mixture which was thenacidified with dilute hydrochloric acid, and extracted with ethylacetate. The extracts were washed with dilute hydrochloric acid, asaturated saline, an aqueous saturated sodium bicarbonate solution and asaturated saline in this order. The resulting organic layer was driedover anhydrous magnesium sulfate, filtrated and concentrated. Theconcentrated residue was purified by silica gel column chromatography(ethyl acetate:hexane=3:7) to give the title compound as white crystals.The yield was 0.43 g (82.7%).

Example 25 Synthesis of 2-chloro-6-n-propylimidazo[1,2-b]pyridazine

Under a nitrogen stream, anhydrous nickel(II) chloride (0.036 g, 0.27mmol) and triphenylphosphine (0.15 g, 0.53 mmol) were added totetrahydrofuran (5.0 ml), and stirred for 1 hour at room temperature. Tothis mixed solution was added 2,6-dichloroimidazo[1,2-b]pyridazine (0.50g, 2.66 mmol), and a solution of n-propylzinc bromide in tetrahydrofuran(0.5 M, 7.98 ml, 3.99 mmol) was added dropwise thereto over 10 minutesunder ice-cooling. The reaction mixture was stirred for 10 minutes underice-cooling, and warmed to room temperature and stirred for 2 hours atroom temperature. Cold water (50 ml) was added to the reaction mixturewhich was then acidified with dilute hydrochloric acid, and extractedwith ethyl acetate. The extracts were washed with dilute hydrochloricacid, a saturated saline, an aqueous saturated sodium bicarbonatesolution and a saturated saline in this order. The resulting organiclayer was dried over anhydrous magnesium sulfate, filtrated andconcentrated. The concentrated residue was purified by silica gel columnchromatography (ethyl acetate:hexane=3:7) to give the title compound aswhite crystals. The yield was 0.46 g (88.5%).

Example 26 Synthesis of 2-chloro-6-n-propylimidazo[1,2-b]pyridazine

Under a nitrogen stream, 2,6-dichloroimidazo[1,2-b]pyridazine (0.50 g,2.66 mmol) and iron(III) acetylacetonate (0.094 g, 0.27 mmol) were addedto tetrahydrofuran (5.0 ml), and a solution of n-propylmagnesium bromidein tetrahydrofuran (2 M, 1.99 ml, 3.99 mmol) was added dropwise over 13minutes to the mixture with stirring at 0 to 10° C. After stirring for10 minutes under ice-cooling, the reaction mixture was warmed to roomtemperature and stirred for 6 hours at room temperature. The reactionmixture was poured onto ice-cold water, acidified with concentratedhydrochloric acid, and extracted with ethyl acetate. The extracts werewashed with dilute hydrochloric acid, an aqueous saturated sodiumbicarbonate solution and a saturated saline. The resulting organic layerwas dried over anhydrous magnesium sulfate, filtrated and concentrated.The residue was purified by silica gel column chromatography (ethylacetate:hexane=3:7) to give the title compound as pale yellow crystals.The yield was 0.28 g (53.8%).

Reference Example 1 Synthesis ofN′-(2,6-dichloroimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-dimethylformamidine

2,6-Dichloroimidazo[1,2-b]pyridazin-3-ylsulfonamide (2.00 g, 6.22 mmol)and N,N-Dimethylformamide dimethyl acetal (1.80 ml, 13.5 mmol) wereheated under reflux for 4 hours in toluene (20.0 ml). The resultingreaction solution was left to cool to room temperature, and concentratedto dryness under reduced pressure to give the title compound as paleyellow crystals. The yield was 2.36 g (100%).

¹H NMR (DMSO-d₆, δ): 2.94 (3H, s), 3.26 (3H, s), 7.71 (1H, d, J=9.5 Hz),8.34 (1H, d, J=9.5 Hz), 8.43 (1H, s).

Reference Example 2 Synthesis ofN′-(2,6-dichloroimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine

N,N-Diisobutylformamide (5.44 g, 34.5 mmol) was dissolved in chloroform(25.0 mL), and under cooling in an ice-sodium chloride bath, phosphorusoxychloride (3.22 mL, 34.5 mmol) was added dropwise thereto at −2° C. orless. After stirring at −2° C. or less for 30 minutes, to the mixturewas added 2,6-dichloroimidazo[1,2-b]pyridazin-3-ylsulfonamide (6.15 g,23.0 mmol). The mixture was stirred at −10° C. for 10 minutes, andtriethylamine (19.3 mL, 138 mmol) was added dropwise over 20 minutes tothe solution at 5° C. or less. The mixture was stirred for 1 hour at 0°C. or less and for 1 hour at room temperature, then poured into anaqueous saturated sodium bicarbonate and extracted 5 times withchloroform. The extracts were combined, dehydrated over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residueswere purified by silica gel column chromatography (ethylacetate:hexane=1:1) to give the title compound as pale yellow crystals.The yield was 5.58 g (59.6%).

mp 151.0-154.0° C.

¹H NMR (CDCl₃, δ): 0.76 (6H, d, J=6.7 Hz), 0.97 (6H, d, J=6.7 Hz),1.90-2.10 (2H, m), 3.23 (2H, d, J=7.6 Hz), 3.28 (2H, d, J=7.7 Hz), 7.26(1H, d, J=9.5 Hz), 7.90 (1H, d, J=9.5 Hz), 8.51 (1H, s).

IR (Nujol, cm⁻¹): 1615, 1456, 1324, 1311, 1146, 910, 858, 654.

Reference Example 3 Synthesis ofN′-(6-chloro-2-trifluoromethylimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-dimethylformamidine

6-Chloro-2-trifluoromethylimidazo[1,2-b]pyridazin-3-ylsulfonamide (1.70g, 5.65 mmol) was suspended in toluene (10.0 ml), andN,N-dimethylformamide dimethyl acetal (90%, 1.84 ml, 12.4 mmol) wasadded thereto and stirred for 3.5 hours under reflux. The reactionmixture was concentrated under reduced pressure. To the residueconcentrated was added diisopropyl ether, and the crystals werecollected by filtration to give the title compound as brown crystals.The yield was 1.96 g (97.4%).

mp 203.7-205.0° C.

¹H NMR (CDCl₃, δ): 2.95 (3H, s), 3.29 (3H, s), 7.79 (1H, d, J=9.6 Hz),8.47 (1H, s), 8.52 (1H, d, J=9.6 Hz).

IR (Nujol, cm⁻¹): 1636, 1526, 1456, 1321, 1201, 1159, 1130, 1115, 922,816, 628, 616.

INDUSTRIAL APPLICABILITY

According to the present invention, it becomes possible to produceeasily and inexpensively an imidazo[1,2-b]pyridazin-3-ylsulfonamidederivative which has a substituent bonded to the 6-position carbon atom,which used to be difficult to produce by a conventional process forproduction, and using the same, sulfonylurea herbicides become possibleto manufacture on a massive scale.

1. A process for producing a compound represented by the formula (II):

wherein X represents a halogen group or an optionally halogenated loweralkyl group, Y represents a hydrogen or SO₂N═CH—NR¹R² wherein R¹ and R²each represent a lower alkyl group, or R¹ and R² may be combinedtogether with the adjacent nitrogen atom to form a heterocyclic ring,and R represents a lower alkyl group, lower cycloalkyl group which maybe substituted with lower alkyl, lower alkenyl group or lower alkynylgroup, which comprises reacting an imidazo[1,2-b]pyridazine compoundrepresented by the formula (I):

wherein X and Y are as defined above, and Z represents a halogen atom orOSO₂R³ (wherein R³ represents an optionally fluorinated lower alkylgroup or phenyl group which may be substituted with lower alkyl), withone or more compounds selected from the organometallic compoundsrepresented by the formula:

wherein R is as defined above, and M¹ represents a univalent metal, M²represents a divalent metal, M³ represents a trivalent metal and M⁴represents a tetravalent metal, and L, L′ and L″ are the same ordifferent and represent an anion, under the presence of a transitionmetal catalyst.
 2. The process according to claim 1, wherein the metalof the transition metal catalyst is palladium, nickel or iron.
 3. Theprocess according to claim 1, wherein the metal of the transition metalcatalyst is nickel.
 4. The process according to claim 1, wherein themetal of the organometallic compound is magnesium or zinc.
 5. Theprocess according to claim 1, wherein R is a lower alkyl group or lowercycloalkyl group which may be substituted with lower alkyl.
 6. Theprocess according to claim 1, wherein X and Z are each a chlorine atom.7. The process according to claim 1, wherein Y is a hydrogen atom and Ris a lower alkyl group.
 8. The process according to claim 3, wherein themetal of the organometallic compound is magnesium or zinc.
 9. Theprocess according to claim 8, wherein the organometallic compound is alower alkylmagnesium halide or a lower alkylzinc halide.
 10. The processaccording to claim 9, wherein the organometallic compound is apropylmagnesium halide or propylzinc halide and the nickel catalyst is[1,3-bis(diphenylphosphino)propane]nickel(II) dichloride orbis(triphenylphosphine)nickel(II) dichloride.
 11. A process forproducing a sulfonamide compound represented by the formula (III):

wherein X represents a halogen atom or an optionally halogenated loweralkyl group and R represents a lower alkyl group, lower cycloalkyl groupwhich may be substituted with lower alkyl, lower alkenyl group or loweralkynyl group, which comprises sulfonating with chlorosulfonic acid acompound represented by the formula (IIa):

wherein X and R are as defined above, which is obtained by reacting animidazo[1,2b]pyridazine compound represented by the formula (Ia):

wherein X is as defined above, and Z represents a halogen atom or OSO₂R³(wherein R³ represents an optionally fluorinated lower alkyl group orphenyl group which may be substituted with lower alkyl), with one ormore compounds selected from the organometallic compounds represented bythe formula:

wherein R is as defined above, and M¹ represents a univalent metal, M²represents a divalent metal, M³ represents a trivalent metal and M⁴represents a tetravalent metal, and L, L′ and L″ are the same ordifferent and represent an anion, under the presence of a transitionmetal catalyst, followed by converting to a sulfonyl chloride withphosphorus oxychloride, then reacting with ammonia.
 12. A process forproducing a sulfonamide compound represented by the formula (III):

wherein X represents a halogen atom or an optionally halogenated loweralkyl group and R represents a lower alkyl group, lower cycloalkyl groupwhich may be substituted with lower alkyl, lower alkenyl group or loweralkynyl group, which comprises hydrolyzing under the presence of acid oralkali a compound represented by the formula (IIb):

wherein X and R are as defined above and Y′ represents SO₂N=CH—NR¹R²(wherein R¹ and R² each represent a lower alkyl group, or R¹ and R² maybe combined together with the adjacent nitrogen atom to form aheterocyclic ring), which is obtained by reacting animidazo[1,2-b]pyridazine compound represented by the formula (Ib):

wherein X and Y′ are as defined above, and Z represents a halogen atomor OSO₂R³ (wherein R³ represents an optionally fluorinated lower alkylgroup or phenyl group which may be substituted with lower alkyl), withone or more compounds selected from the organometallic compoundsrepresented by the formula:

wherein R is as defined above, and M¹ represents an univalent metal, M²represents a divalent metal, M³ represents a trivalent metal and M⁴represents a tetravalent metal, and L, L′ and L″ are the same ordifferent and represent an anion, under the presence of transition metalcatalyst.